Pathophysiology of acute

infectious encephalitis

Thomas de Broucker, MD
Service de Neurologie
Hpital Delafontaine
Saint-Denis, France
 OBJECTIVE
understand the pathophysiology of acute infectious encephalitis

What makes the brain vulnerable to a foreign organism

aggression ?

What makes a microorganism able to infect the CNS (brain &

meninges) ?

What makes a microorganism target specific structures or cell

types of the CNS ?

What are the CNS lesions due to acute encephalitis ?

Micro-organism
+ Brain

Immune system

CNS manifestations
1. The brain, its accessories and the
immune system
 The CNS cells (1/2)
Neurons
Specialized cells in specialized areas

Neuroglial cells
Astrocytes participate
To the maintenance & structure of the brain
To the neuromediator homeostasis
To the blood-brain barrier (BBB)
To the innate hosts immune response
To the wound healing (astroglial scar)
Oligodendroglial cells : myelin sheath
Ependymal cells : ventricular lining
Microglial cells
Resident antigen-presenting cells
Participate to the innate and adaptative immune responses
 The CNS cells (2/2)

Nonglial cells
Cerebrovascular endothelial cells (CVE)
Perivascular and plexus choroid endothelial cells
Macrophages and dendritic cells
Leptomeningeal cells

Blood-derived leukocytes trafficking cells

Lymphocytes
Vessels and Blood-Brain Barrier

Capillary level
 The BBB at the postcapillary level

Inner vascular basement membrane

Outer vascular basement membrane
Glia limitans basement membrane
fused gliovascular membrane
The CSF flow
From the chorod plexuses
Lateral, 3rd, 4th ventricles
Posterior fossa cisterns
Basal cisterns of the skull
Pericerebral subarachnod spaces
Paccioni granulations
to the brain venous sinuses
How the brain defends itself

The immune system of the brain

 Immunology of the CNS :
the brain is an immunologically specialized organ

Foreign organisms have a limited access to the brain

Immune response must be less noisy than in other organs :

Brain poor ability to support swelling
Limitation of neuronal destruction

APC have a limited surface expression of MHC => reduction

of the immune response

There are no resident adaptative immune cells into the CNS

The steps of the CNS innate immune response
(once a microorganism succeed to invade)

1. Recognition of pathogens-associated molecular patterns

by the Toll-like Receptors (TLRs) of microglial cells and
astrocytes
Single and double stranded viral RNA
Bacterial lipopolysaccharides, etc.

2. Activation of the TLR-wearing cells, leading to :

Production of NO and IFN alpha and beta
Expression of MHC on microglia, perivascular macrophages and
astrocytes
Cytokines & chemokines production by microglia and astrocytes

3. Activation of cerebrovascular endothelial cells

 Cytokines and chemokines
Cytokines : proinflammatory signals (IL-1, IL-6, TNF-
alpha) sent to target cells (ie CVE cells)

Chemokines : target migratory cells

Mononuclear phagocytes, T lymphocytes
CCL2 (MCP-1), CCL3 (MIP-beta), CCL5 (RANTES), CXCL10
(IP10)

CVE cells products

Intercellular adhesion molecules
Entry of systemic
Vascular cell adhesion molecules
immune system cells
Matrix metalloproteinases
 1 2
Ag detection cytokines + chemokines Matrix metalloproteases + APC
increase of the BBB permeability parenchymal migration
+ cell rolling, adhesion, migration
 The adaptative immune system
CNS invasion by immunocompetent cells in
response to cytokines and chemokines stimulation
In order of appearance :
NK cells
Antigen-specific CD8+ and CD4+ T cells
B cells
Monocytes and macrophages
Meningeal & parenchymatous inflammation
Objective : clearance of the foreign microorganism
Micro-organism
infection + Immune system

Brain lesions
 Primary lesions due to infection vary
depending on
- the particular/cellular tropism of the microorganism
- the magnitude of the inflammatory response

Destructive phagedenic process = abscess

Neuronal dysfunction / death
Oligodendrocyte dysfunction / destruction
Astrocyte transformation / destruction / gliosis
Ependymal necrosis
Infiltration of inflammatory cells
Infectious granuloma
Vasculitis
 CNS lesions due to secondary insults

Brain edema and compression of healthy structures

(herniation) and microvasculature
Hydrodynamic-induced damage (hydrocephalus)
Infarction (arterial or venous)
Hypoxic anoxic damage
Convulsive status
Intracranial hypertension
Systemic cardiac/pulmonary deficiency

CNS lesions clinical manifestations of encephalitis

headache, seizures, focal deficits (motor, sensory, cognitive), consciousness decrease, etc.
2. The micro-organisms
Bacteria
Viruses
Fungi
Parasites
The neurotropism of micro-organisms
All the foreign micro-organisms do not invade the CNS

The different routes of neuroinvasion

Directly (vicinity)
By the blood stream
Blood choroid plexuses CSF brain
Blood meninges CSF brain
Blood brain
By neuronal axonal & trans-synaptic pathway

Neurotropism and different cell tropisms are organism

specific
 Different target cells of the CNS
Neurons : polioencephalitis/myelitis
neuronal death & neuronophagia
Cortex
Basal ganglia = grey
Motor neurons
= white
Glial cells : leukoencephalitis
Oligodendrocytes demyelination
Astrocytes BBB dysfunction, astrogliosis
Ependymocytes ventriculitis
Microglia microglial nodules

All types of CNS cells : panencephalitis

 Other targets into the CNS

Chorod plexus
Meninges and CSF
Leptomeninges
Pia mater
Arachnod
Pachymeninges (dura mater)
Vessels
Vasculitis
Some examples of encephalitis pathophysiology
Viruses
Herpes simplex 1 panencephalitis
Varicella Zoster Virus encephalitis
Enterovirus and arbovirus polioencephalitis
HIV
Rabies

Bacteria
Mycobacterium tuberculosis
Listeria monocytogenes

Parasites
Malaria

Fungi
Cryptococcosis
Aspergillosis
 Neurotropic
Viruses

Schweighardt & Atwood. J Neurovirol;7:187-195

Virus entry strategies.

J Cell Biol.2011;195:1071-1082
 HSV-1
Route of entry
Reactivation of latent infection
Trigeminal ganglion
Other sites of latent CNS virus (olfactory bulb, pons, medulla)
Direct neuroinvasion (olfactory sensory cells)
Hematogenous spread during viraemia (prodromal phase)

Cell infection involves

Viral glycoproteins (gB, gC, gD, gH, GL)
Neuronal surface molecules (heparan sulfate, HVEM, nectin 1 &
2)
neuron
After cell entry
HSV is a DNA virus :
nuclear invasion
DNA replication
DNA expression & protein production

Host cell lysis

Virus spread & mutiple cell type infection (panencephalitis)
MHC expression and immune system recruitment

Massive inflammatory response

dema and Necrosis
Detersion
 HSV1 meningoencephalitis
an acute necrotizing panencephalitis
Early phase Full-blown infection

sequelae
 HSV encephalitis and auto-immunity
Anti-NMDAR antibodies are observed in the blood, CSF or both during the
acute-subacute phase of the encephalitis in 30% of the cases, but not during
EV and VZV encephalitis
44 cases
IgG, IgA and IgM
Variable kinetics

No clinical difference
between Ab+ and Ab- groups

Prss et al. Ann Neurol.2012;72:903-911

Relapses are frequently linked to the occurrence of anti-NMDAR Ab

Mainly described in children
Could account for half of the cases Hacohen et al. Mov Dis.2013;20:90-96
 Herpes virus encephalitis is a trigger of
autoimmunity Armangue et al. Ann Neurol 2014;75:317323

4 children (+1 adult) having a

HSVE relapse (delay 7-41 days)

34 retrospective cases of HSVE tested after 1week

3 : anti NMDAR positive, all relapsing
10 : other unknown neuronal surface antibody

Mechanism of antibody production :

Molecular mimicry ?
Antibody production secondary to neuronal lysis and antigen release ?
VZV meningoencephalitis pathophysiology

Context : VZV primary infection or reactivation

Meningeal inflammation
Brain swelling
Parenchymal VZV infection
- Present in varicella encephalitis
- Uncertain in VZV reactivation encephalitis
Focal vasculitis of different vessel sizes with
endothelial and smooth muscle in vessel walls
infection

Role of immunocompromission
Elderlies
Lymphoma & cancer
Immunosuppressant drugs
AIDS
 VZV vasculopathies
Zoster ophtalmicus &
Multifocal (AIDS) contralateral hemiplegia
Demyelinating meningoencephalitis

A
I
D
VZ reactivation & infection of : S
Astrocytes
Oligodendrocytes
Ependymocytes
Endothelial cells

Ventriculitis
 Enterovirus polioencephalitis

RNA viruses
Enterovirus (70,71)
Poliovirus (1, 2, 3)
Cocksackie (A4, A7, B3)
Echovirus (2, 9, 30)

Poliovirus Inflammation, microglial nodules, neuronophagia Cocksakie

 Multiple routes of CNS invasion (after fecal-oral transmission)
BBB crossing during viremia
BBB crossing by EV-infected immune cells : (Trojan horse)
Neuronal centripetal spreading from damaged muscle nerve terminals

Specific CNS neurotropism (neuronal, glial & meningeal)

Poliovirus binds to cell receptor CD155 of :
All neurons including ganglionic sensory cells ; astrocytes &
oligodendrocytes
pyramidal tract and spinal cord anterior horn Polio virus
EV 71 (cell receptor SCARB2) :
Neurons & astrocytes
Basal ganglia and pyramidal systems, reticular formation
Coxsackie (cell receptor CAR) :
Neuronal progenitor cells and neurons CD155
Choroid plexus, neurogenic regions, hippocampus, cortex

Role of humoral immunity defect in Echovirus encephalitis

 Meningo
Polio
Encephalo
Myelitis
due to Enterovirus

GM involved
WM spared
Exemple of Arbovirus encephalitis : Japanese encephalitis

Mosquito sting

N Hematogenous invasion
E
U
R Infection of
O
Meningeal,
& Neuronal
Endothelial cells
N
E
U Polio-encephalitis
R Brain & cerebellar cortex,
O
basal ganglia,
N
O substantia nigra,
T thalamus,
R hippocampus,
P
pons, medulla oblongata
I
S spinal cord anterior horn JEV
M
 HIV
Route of entry
early contamination of CNS : primary encephalitis resting virus
during AIDS : Trojan horse (mononuclear phagocytes) + direct invasion
CNS cells targets = microglial cells & astrocytes

During the primary infection During full-blown AIDS During controlled systemic but
not CNS HIV infection

Different forms of neuropathology :

Leukoencephalitis
Poliodystrophy due to host & viral toxic factors
IRIS (CD8 massive infiltration)
 Rabies
Infection through a skin/muscle wound (dog bite)
Neurotropism
Slow rate replication in muscle fibers
Entry through nicotinic receptor of motor endplate
Sensory/autonomic skin innervation (?)
Retrograde axonal transport to the spinal cord
Cell to cell and transsynaptic ascending spreading
Brain neuronal infection (caudal-rostral polio-encephalitis)
Centrifugal dissemination from the brain to the innervated
organs (skin, salivary glands, myocardium,)
Furious rabies

Paralytic rabies
Lancet Neurol 2013; 12: 498513
Bacteria
 Mycobacterium tuberculosis

Low-level bacteriemia infection of microvessels endothelial

cells caseating vascular focus (Rich focus)

Meningeal or parenchymatous location

Release of MT and dissemination meningitis, encephalitis,

tuberculoma, abscess
 Tuberculous meningoencephalitis
Dense gelatinous inflammatory exsudate
Most florid in the basal cisterns (as a result of the flow pattern of CSF)
Prepontine and around the spinal cord
Surrounding nerves and arteries (vasculitis)
Impairment of CSF flow

meningeal exudate of macrophages, lymphocytes, plasma cells, and fibrin

 Listeria monocytogenes

Route to brain/meningeal infection

Haematogenous spread from gut meningitis
Neuronal spread : rhombencephalitis
Haematogenous dissemination neuronal infection (cranial
nerves) cell-cell and axonal CNS spreading
oral mucosa trigeminal nerve brainstem

Role of immunosuppression
in the initial phase of infection
Parasites
 Cerebral malaria
Plasmodium falciparum infection causing a global CNS dysfunction
Sequestration of parasitized red blood cells in the brain
microvasculature : engorgement of small vessels
Deposition of Ag-Ab complexes, endothelial damage and platelet
aggregation : edema, capillary necrosis, perivascular haemorrhages

Haemorrhage centered by a necrotic blood vessel Drck granuloma

Cell-mediated immune inflammatory response : parenchymal and

meningeal inflammation
 Fungi
Route of infection
Inhalation, skin wound or gut translocation
Brain invasion : haematogenous route or direct from infected sinus air
or bone

Immunocompromission is frequent
Cryptococcus neoformans, Candida sp., Histoplasma capsulatum,
Blastomyces dermatidis, Aspergillus sp.

Lesions : basal meningitis, parenchymal granulomas and

abscesses, vascular infiltration / obstruction
 LESIONS
Yeast Branching hyphae Pseudo hyphae

Leptomeningitis Large vessels Microvasculature

obstruction obstruction

Blastomyces Aspergillosis Candida sp.

Candida Cladosporium
Coccidioides Fusarium
Cryptococcus Mucormycosis
Histoplasma Allescheria boydii
Paracoccidioides
Sporotrichum
Torulopsis
Aspergillus fumigatus Exserohilum rostratum
 conclusion
As many microorganisms, as many
pathophysiologies of the encephalitis